In order to play effective defense, you have to read your opponent's tendencies. Some plays that are great against some people are going to be garbage against others.
But in order to determine what will work, you need to figure out your opponent's Tendencies.
Where does your opponent throw the ball when he has time?
Does he hit the seams? If so, you may want to move LB's overtop of the TE (or slot receiver) and maybe even man him up.
Does he go for the corners? If so, you may want to consider more buzz (purple) zones.
Does he use 10-yard curls? Purple zones and outside hook zones will help with this. Be sure to bump as well.
Does he use a deep post to get behind your coverage? Make it a habit to play with your coverage to help throw off his reads to prevent this.
Does your opponent like to roll out? If so, what side does he favor?
This will help you determine where to send pressure from, how to blitz your linemen, etc.
Where does your opponent throw when under pressure?
Will he throw to the shallow middle? If so, use more plays that have 2-3 guys in the middle with hook zones in the default play art.
Will he go to the flats? Corners in flat zones are great for this.
Does he use unbalanced formations often?
If so, make sure you have purple zones on that side. He will likely set up a route combo to that side.
How often does he use screens?
Try to figure out what formations he uses and who the screen goes to. Some people will roll way out to the opposite side. Stop chasing him and read the screen. I see a lot of people run HB Screens out of Shotgun and Singleback sets. If they’re in the Shotgun formations I always manually blitz from the that the HB is on, If I see him stop I’ll recover from my blitzing with the OLB/SS and recover to shut down the screen. As far as WR Screens go, a 2 deep coverage with man coverage under is the way to go.
Can your opponent run out of Shotgun?
This will determine if you can safely move guys out of the box when he's in Shotgun.
Does he use compressed sets?
Remember to move your flats zones out a little if he does. Compressed sets will enable him to throw quick slant-outs if you don't do this. And use buzz zones only to the boundary-side to better control zone holes.
Does your opponent do better against max coverage, or pressure?
Some people are great against the blitz, but are terrible when seeing F@G D. Others rely on having time to throw and will take some sacks. And some people are good against both. Figure out what is more successful and lean more towards that.
(H/T: Michura over at the Madden Boards)